The binding of radiolabeled modified glycoproteins to parenchymal and nonparenchymal cell preparations isolated from the perfused rat liver has been studied. Hepatocytes possess receptors for glycoproteins with galactose as the terminal sugar residue. Non-parenchymal cells lack a receptor for galactose-terminated glycoproteins but specifically bind N-acetylglucosamine and mannose-terminated glycoproteins. The effect of modifying the carbohydrate moiety of glucocerebrosidase on the distribution of its cellular uptake after intravenous infusion into rats was studied. The carbohydrate moiety of this enzyme could be modified without loss of enzyme activity. Galactose-terminated glucocerebrosidase was selectively taken up by hepatocytes. Exposure of n-acetylglucosamine or mannose residues markedly augmented the uptake of the enzyme by Kupffer cells. The ability to manipulate the cellular distribution of an infused enzyme may be of importance in enzyme replacement therapy. The intact glycoprotein, human beta-hexosaminidase A is rapidly cleared from the circulation by a mannose-specific recognition system on hepatic sinusoidal cells. This process may be of physiologic importance in preventing the accumulation of potentially autodestructive lysosomal enzymes in the circulation.